ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

 描述（由申请人提供）：提高原发性开角型青光眼患者的视网膜神经节细胞（RGC）存活率是该疾病患者的基本治疗目标，但迄今为止，尝试降低继发于手术或药物的眼内压（IOP）是唯一临床批准的方法。需要直接保护RGC免受神经性昏迷损伤的主要神经保护疗法，但尚未推进到临床，主要是因为定义这种疾病的复杂的泛细胞病理学可能需要能够同时作用于多种损伤机制的多效性疗法。通过非损伤性应激诱导适应性、多因素“条件反射”反应可能代表了这样一种治疗方法，鉴于其在视网膜缺血和光毒性临床前模型中证明的有效性的跟踪记录，以及心肌缺血和中风条件反射的临床试验的运行。事实上，我们最近发现，在诱导为期3周的实验性青光眼之前，将小鼠暴露于一系列轻度的全身性缺氧应激，可对RGC索马和轴突提供强有力的保护。本文提供的初步功能和形态学发现证明了类似的稳健保护，即使在疾病发作后出现重复缺氧刺激时。这种对青光眼“后调节”的表观遗传反应形成了本申请的基础，并且我们的研究将由以下具体目标指导。 具体目标1：使用我们的实验性青光眼的诱导模型，测试以下假设：重复低氧后处理（HX-Post）提供的RGCs的结构和功能保护随着疾病和治疗的进展而持续。 具体目标二：在我们的诱导型青光眼模型中，检验相关假设，即使用临床批准的药物去铁胺（DFX-Post）进行重复的药理学后处理也将对RGCs提供持续的形态和功能保护。DFX通过稳定转录因子缺氧诱导因子-1 α（HIF-1α）保护RGCs的假说也将得到验证。 具体目标3：在青光眼的DBA/2 J遗传模型中，检验以下假设：在7.5-12.0月龄之间给予HX-Post和DFX-post将对“终末期”RGC疾病表型（结构和功能、体细胞和轴突）产生积极影响。 具体目标4：使用遗传学和药理学方法，在我们的诱导模型中检验HX-Post介导的严重依赖于HIF-1α基因靶点CCL 2（MCP-1）的假设。 在两种不同的青光眼模型中记录继发于重复的生理或药理学后处理的RGC功能和结构的持续改善，将为以下概念提供强有力的概念验证、预防性有希望的证据：一系列基于先天表观遗传学的保护性反应（其中一些我们将在这里揭示）可以被激活以保护人类青光眼中的RGC。

 DESCRIPTION (provided by applicant): Enhancing retinal ganglion cell (RGC) survival in primary open-angle glaucoma is the fundamental treatment goal for patients with this disease, but to date, attempts to reduce intraocular pressure (IOP) secondary to surgery or drugs is the only clinically-approved approach. Primary neuroprotective therapies that directly protect RGCs from glaucomatous injury are desired, but have yet to be advanced to the clinic, largely because the complex, pan-cellular pathology that defines this disease will likely require a pleiotropic therapy capable of acting on multiple injury mechanisms concomitantly. Inducing an adaptive, multi-factorial "conditioning" response by a noninjurious stress may represent one such therapeutic approach, given its track record of demonstrated efficacy in preclinical models of retinal ischemia and phototoxicity, and the run of clinical trials of conditioning for myocardial ischemia and stroke. In fact, we recently showed that exposing mice to a series of mild systemic hypoxic stresses prior to inducing a 3-wk period of experimental glaucoma afforded robust protection of RGC soma and axons. Preliminary functional and morphologic findings provided herein document similarly robust protection even when the repetitive hypoxic stimulus is presented after disease onset. This epigenetic response to glaucoma "postconditioning" forms the basis of the present application, and our studies will be guided by the following specific aims. Specific Aim 1: Using our inducible model of experimental glaucoma, test the hypothesis that the structural and functional protection afforded RGCs by repetitive hypoxic postconditioning (HX-Post) is sustained as the disease and treatment progress. Specific Aim 2: In our inducible glaucoma model, test the related hypothesis that repetitive pharmacologic postconditioning with the clinically-approved drug deferroxamine (DFX-Post) will also afford sustained morphologic and functional protection of RGCs. The hypothesis that DFX protects RGCs via stabilization of the transcription factor hypoxia-inducible factor-1α (HIF-1α) will alsobe tested. Specific Aim 3: In the DBA/2J genetic model of glaucoma, test the hypotheses that HX-Post, and DFX-post, administered between 7.5-12.0 months of age, will positively impact 'end-stage' RGC disease phenotypes (structural and functional, somal and axonal). Specific Aim 4: Using genetic and pharmacologic approaches, test in our inducible model the hypothesis that HX-Post-mediated is critically dependent on the HIF-1α gene target CCL2 (MCP-1). Documenting sustained improvements in RGC function and structure in two distinct glaucoma models secondary to repetitive physiologic or pharmacologic postconditioning will provide strong proof-of-concept, translationally-promising evidence for the notion that a spectrum of innate epigenetics-based protective responses, some of which we will reveal here, can be activated for RGC protection in human glaucoma.